The discovery of fetal DNA in maternal plasma in 1997 has opened up new possibilities for noninvasive prenatal diagnosis (Lo et al Lancet 1997; 350: 485-487). This technology has been rapidly translated to clinical applications, with the detection of fetal-derived, paternally-inherited genes or sequences, e.g. for fetal sex determination and for fetal RhD status determination. However, prenatal diagnostic applications involving genomic targets which are present in both the maternal and fetal genomes, e.g., chromosome 21, are much more challenging.
Recently, it has been demonstrated that single molecule counting techniques, with their superior quantitative precision, might be a promising solution for this problem (Lo et al Proc Natl Acad Sci USA 2007; 104: 13116-13121; Fan et al Anal Chem 2007; 79: 7576-7579; U.S. patent application Ser. No. 11/701,686; Chiu et al Trends Genet 2009; 25: 324-331; Chiu et al Proc Natl Acad Sci USA 2008; 105: 20458-20463; Fan et al Proc Natl Acad Sci USA 2008; 105: 16266-16271). Such methods achieve diagnostic goals through the observation of quantitative differences in the number of molecules from selected genomic locations between disease and health. For example, for the diagnosis of fetal Down syndrome, the number of molecules from chromosome 21 will be increased when the fetus is suffering from trisomy 21 (Chiu et al Proc Natl Acad Sci USA 2008; 105: 20458-20463; Fan et al Proc Natl Acad Sci USA 2008; 105: 16266-16271).
However, such counting techniques may suffer from a limited number of data points or other disadvantages. Therefore, it is desirable to provide new methods, systems, and apparatus for performing prenatal diagnosis having certain advantages over existing techniques.